The present invention relates to nitroxy derivatives of the hydroxybenzoic acid in a modified physical form, and the pharmaceutical formulations thereof, said derivatives having general formula
Axe2x80x94X1xe2x80x94NO2xe2x80x83xe2x80x83(I)
wherein A is an hydroxybenzoic acid derivative as defined hereunder; X1 is a linking bivalent radical as defined hereunder, said formulations capable to induce in very short times, of the order of 2-2.5 hours, the plasmatic concentration peak of the hydroxybenzoic acid derivative, defined as A.
The compositions of the invention can be used to prepare oral dosage forms suitable to induce a fast beginning of the pharmacological effect.
As well known the pharmacologically active substances when administered per os produce a systemic effect only after having undergone an absorption process through the gastroenteric duct walls. The drug absorption process is a complex phenomenon which depends on various factors, among which drug liposolubility and hydrosolubility. It is difficult to theoretically foresee, in practice it is impossible to know which is the optimal combination of these factors to obtain the maximum absorption peak of the active principle in short times, of about 2-2.5 hours at most.
Generally the therapeutic effect of a drug which shows its activity by systemic route when administered per os depends, in particular, on the following factors:
drug absorption through the gastrointestinal wall,
concentration in the hematic fluid,
possible interaction whith the target tissue.
In particular for the drugs having an antiinflammatory and analgesic activity, an essential feature is the action quickness, i.e. the effect onset has to show in relatively short times after consumption.
The nitroderivative compounds of formula (I), in the unmodified physical form according to the present invention, are known from the patent applications WO 95/30641 and WO 97/16405 in the name of the Applicant. These compounds with respect to the antiinflammatory precursor drugs have a global comparable or higher efficacy, but they have the advantage to show lower side effects. The drawback of these products is that they do not show chemical physical properties such as to allow an haematic peak of maximum absorption in the period of time of 2.5 hours at most. Pharmacokinetic studies carried out by the Applicant using a conventional pharmaceutical formulation for oral use of the nitroderivative compounds of formula (I), not treated as reported in the present invention, have shown that there is no haematic concentration peak in the above mentioned short times, therefore the product does not timely show its therapeutic properties. See the Examples showing that the haematic peak takes place after too long times from the consumption, of about 6 hours.
The need was felt to have available pharmaceutical compositions for oral use, comprising the nitroderivative compounds of formula (I), such as to produce a maximum plasmatic concentration peak (Cmax) in short times, such that tmax (tmax being the time at which Cmax occurs) is of about 2.5 hours at most, preferably lower than or equal to 2 hours.
It has been found by the Applicant that it is possible to solve this technical problem with the compounds and formulations thereof for oral use as indicated hereinafter.
An object of the present invention are compounds of formula (I) and pharmaceutical compositions for oral use comprising as active principle said compounds
Axe2x80x94X1xe2x80x94NO2xe2x80x83xe2x80x83(I)
wherein
A=R(COX),
X=O, NH, NR1C, wherein R1C is a linear or branched C1-C10 alkyl, R is selected from the following radicals: 
wherein
R1 is a OCOR3 group; wherein R3 is methyl, ethyl or linear or branched C3-C5 alkyl, or the residue of a saturated heterocyclic ring having 5 or 6 atoms, which can be aromatic or completely or partially saturated, said heterocyclic ring containing one or more heteroatoms independently selected between O and N;
R2 is hydrogen, hydroxy, halogen, linear or branched when possible C1-C4 alkyl, linear or branched when possible C1-C4 alkoxyl; linear or branched when possible C1-C4 perfluoroalkyl, for example trifluoromethyl; monoxe2x80x94or dixe2x80x94(C1-C4) alkylamino;
R1 and R2 together are the dioxymethylene group, with the proviso that when X=NH, then Y is ethylene and R2 =H as defined hereinder;
R1 cannot be OCOR3 in position 2 when R3 is methyl;
nI is an integer and is ) or 1.
Preferably in (Ia X=0, R1 is acetoxy and is in ortho position with respect to the -CO- group, R2 hydrogen; preferably in Ib) R3=CH3, nI=0; X is equal to O, and the bond of the aromatic ring with the COX group is in the 1 or 2 positions;
X1 is a bivalent linking bridge selected from the following:
YO:
Y=linear or branched when possible C1-C20, preferably
C2-C5, alkylene; or
C5-C7 cycloalkylene optionally substituted;
or X1 is selected from the following: 
wherein n3 is an integer from 0 to 3, n3xe2x80x2 is an integer from 1 to 3; 
wherein n3 and n3xe2x80x2 have the above mentioned meaning; 
wherein nfxe2x80x2 is an integer from 1 to 6, preferably from 1 to 4; 
wherein R1f=H, CH3 and nfxe2x80x2 is as above defined; said compounds of formula (I) being completely or partially in amorphous form.
The amorphization degree can be measured by well known methods such as for example DSC, RX, IR, etc. For partially amorphous it is meant that in the pharmaceutical compositions of the invention the compounds of formula (I) are generally amorphous for at least 5%, preferably 10%, more preferably for at least 80%, as measured by DSC.
The amorphization degree is determined by DSC as variation reduction) of the subtended area of the endothermic melting peak of the active principle. When the amorphization is complete, the melting peak characteristic of the active principle of formula (I) substantially disappears. This means that there is a variation of the enthalpy associated to the melting peak.
A test for measuring the amorphization degree according to the present invention is the following: an amount of nitroderivative of formula (I) is added with hydroxypropyl-xcex2-cyclodextrin in the molar ratio 1:2; 43 g of the compound of formula (I) are dissolved in 5 l of ethyl alcohol; the so obtained organic solution is mixed at room temperature with 5 l of deionized water containing 7% w/v (350 g) of hydroxypropyl-xcex2-cyclodextrin. The hydroalcoholic solution is treated in the spray-drying LabPlant SD-05 Spray-Drying equipment, with an hot air flow at the inlet at the temperature of 60xc2x0 C., maintaining an air flow such as to allow outlet temperatures of about 45xc2x0 C.; the crystallinity loss is evaluated on the powder (5-10 mg) by the DSC method and the variation of the peak area is determined by comparing the area with that of the precursor treated under the same conditions without the addition of cyclodextrin.
An indicative test of the crystallinity decrease of the compounds of formula (I) is based on the determination of their dissolution rate in water.
The dissolution rate test is carried out in a dissolving equipment according to United States Pharmacopeia 23 by using a volume of deionized water of 1000 ml. The blade stirrer speed is of 100 rpm and the temperature is 37xc2x10.5xc2x0 C.
In a little glass vessel an exact amount of each sample is weighed so that it contains an amount of the active principle equal to 30 mg, which is directly introduced in the vessel containing the deionized water. At predetermined times, respectively of 5, 10, 15, 30, 45, 50, 60, 90 and 120 minutes from the beginning of the test, the amount of the nitroderivative compound passed in solution is determined, by measuring the concentration w/v (weigh/volume) thereof by UV spectrophotometry at the wave length of 235 nm, using a calibration line. The data are expressed as percentage of nitroderivative compound passed in solution in connection with the time. The amount of the compound of formula (I) passed in solution at the time of 10 minutes is at least about 10 times higher with respect to that of the nitroderivative compound not in amorphous form.
As said, the formulations of the invention are surprisingly and unexpectedly capable to induce in very short times, in the order of 2-2.5 hours, the plasmatic concentration peak of the hydroxybenzoic acid derivative A.
Preferably in the compounds of formula (I) R=(Ia), X=O and X1 is the aromatic radical of formula (PAI) wherein n3xe2x80x2=1 and n3=0; said preferred compounds having the following general formula (IA1): 
wherein R1 and R2 are as above defined.
The ester of formula (Ia1) wherein the nitroxymethyl group is on the aromatic ring in meta position, or position 3, with respect to the carbon atom bound to the oxygen of the ester group, is preferred.
The Applicant has surprisingly and unexpectedly found that when the nitroderivatives of formula (I) are present in the pharmaceutical compositions of the invention in a completely or partially amorphized form, in consequence of gastrointestinal absorption, high plasmatic concentrations are obtained in very short times, the maximum plasmatic concentration peak is obtained in a period of time of 2.5 hours at most.
The partially or completely amorphized nitroderivative compounds of formula (I) are obtainable by treating the nitroderivatives with one or more excipients, capable to amorphize said nitroderivatives.
The techniques used for the amorphization are for example co-grinding, kneading, spray-drying, lyophilization, preferably spray-drying and co-grinding.
In particular in the spray-drying technique the active principle is dissolved in a solvent, for example alcohols, and the so obtained organic solution is mixed at room temperature with a solution or suspension of the excipient capable to give amorphization of the compounds of formula (I). The solution or suspension resulting after mixing is treated in a spray-drying equipment. For this and the other techniques see the specific Examples.
Excipients preferably belong to one or more classes mentioned hereinafter: C5-C6 polyalcohols, mono- and disaccharides and their derivatives, oligosaccharides containing from 3 to 10 saccharide units and their derivatives, polysaccharides, their derivatives including their salts, cyclodextrins and their derivatives, non cyclic cyclodextrin analogues, for example non cyclic derivatives of xcex2-cyclodextrin, polymers and copolymers of vinyl-based monomeric units, and/or containing a carboxylic function, or (meth)acrylic monomers.
Examples of C5-C6 polyalcohols are sorbitol, mannitol; examples of monosaccharides and their derivatives are glucose, fructose, mannose, galactose glucosamine; example of disaccharides are lactose, saccharose, maltose etc; examples of polysaccharides and their derivatives are microcrystalline cellulose, hydroxypropylcellulose, hydroxyethylcellulose hydroxymethylcellulose, methylcellulose, ethylcellulose carboxymethylcellulose, and their salts, preferably sodium and calcium salts, and their crosslinked forms, cellulose acetate, cellulose acetophthalate and their ethers, for ex. cellulose phthalate hydroxypropylmethyl ether, starch and derivatives such as for example sodium carboxymethylstarch, soluble starch, pregelled starch; examples of cyclodextrins and derivatives thereof are dimethyl-xcex2-cyclodextrin, 2-hydroxy-ethyl-xcex2-cyclodextrin, 2-hydroxypropyl-xcex2-cyclodextrin, 3-hydroxypropyl-xcex2-cyclodextrin, trimethyl-xcex2-cyclodextrin.
An object of the present invention are the pharmaceutical compositions for oral use containing as active principle the partially or completely amorphized compounds of formula (I) and comprising at least one of the above mentioned excipients.
It has been found by the Applicant that the formulations of the invention show an improved dissolution rate in water, determined by the above described dissolution test.
In the compositions according to the present invention the ratio between the amount by weight of nitroderivatives of formula (I) and that of the excipients capable to amorphize the nitroderivatives is generally in the range 1:20 and 1:0.5, preferably 1:0.7 and 1:10.
As said, the formulations for oral use of the present invention are capable to induce in very short times, of the order of 2-2.5 hours, the plasmatic concentration peak of the hydroxybenzoic acid derivative as defined in A, and it has also been found that they are capable to produce the following pharmacokinetic effects:
to increase the plasmatic CMAX (maximum concentration) of the hydroxybenzoic acid derivative as defined in A, after single administration, with respect to the untreated (not amorphized) product according to the present invention;
to increase of at least 20%, preferably of 50%, the area substended from the curve of the plasmatic concentrations in the range 0-3.5 hours from the administration.
When in the partially or completely amorphized product of formula (I) R=(Ia) the hydroxybenzoic acid derivative as defined in A is the salicylic acid (see the Examples).
The nitroderivative compounds of formula (I) wherein R is a radical of formula Ia) or Ib) are obtainable according to the known methods in the prior art. See for example the methods described in the patent applications in the name of the Applicant WO 95/30641, WO 97/16405, or in the international patent application PCT/EP00/00353.